Pancreatic cancer (PC) remains one of the most deadly cancers, with a dismal 5-year survival rate of less than 5%. Endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA) cytology is often performed to obtain a pathological diagnosis of suspicious pancreatic solid and cystic lesions to guide further management of patients (i.e., preoperative surgical planning or neoadjuvant treatment). However, cytology is often stymied by the average sensitivity of 80% for pancreatic solid lesions and even more dismal sensitivity of less than 30% for diagnosing malignancy in cystic lesions. The efficacy of existing tumor markers also remains sub-optimal. The major objective of this application is to explore endogenous microscopic spectral markers as potential biomarkers to improve the diagnostic accuracy of malignancy on pancreatic solid and cystic lesions. To achieve this goal, we will address the development of a novel optical instrument - multi-mode multi- dimensional partial-wave spectroscopic microscopy (MD-PWS) that provides a comprehensive assessment of multi-dimensional elastic light-scattering signals that contain a full set of 3D wave-vectors at sub-cellular or molecular level. We hypothesize that MD-PWS derived microscopic spectral markers will detect subtle structural alterations in cytologically non-malignant-appearing cells from patients with pancreatic cancer and pancreatic cyst that carries a high malignant potential, more sensitive than conventional cytology or other clinically available biomarkers. We will explore the feasibility of MD-PWS microscopic spectral markers to improve the cytological diagnosis of malignancy in pancreatic solid lesions as well as cystic lesions. MD-PWS derived microscopic spectral markers will also provide significant insights into the structural characteristics of pancreatic cells at sub-cellular level. The results from this project will serve as a justification for a multi-center collaboration to fully evaluate this technology in a clinical setting. Our long-term goal is to develop a simple, cost-effective and highly sensitive microscopy system to improve the diagnostic accuracy and development of risk stratification strategies for pancreatic cancer. Ultimately, our proposed technology could also lead to development of better diagnostic protocols for a wide variety of cancers. PUBLIC HEALTH RELEVANCE: This project is significant to the public health issue of diagnosis and early detection of pancreatic cancer. The accurate diagnosis of pancreatic solid and cystic lesions is clinically challenging. A highly sensitive microscopy system to improve the diagnostic accuracy for pancreatic malignancy and high-risk cystic lesions that have a high malignant potential could help the development of risk stratification and prevention strategies for pancreatic cancer.